Grandiosity Hallucinations Paranoia Delusions

Antipsychotic drugs
(Neuroleptics, Major tranquillizer; Ataractic)
Dr. S.
 Antipsychotic drugs
• Antipsychotic drugs (also called neuroleptics/ major
tranquilizers/ ataractic) are used primarily to treat
schizophrenia (a biologic illness), but they are also effective in
other psychotic states, including manic states with psychotic
symptoms such as grandiosity, paranoia, and hallucinations, and
delusions.
• Antipsychotic drugs are not curative and do not eliminate
the chronic thought disorder, but they often decrease the
intensity of hallucinations and delusions and permit the
person with schizophrenia to function in a supportive
environment.
 Tranquilizers
• Tranquilizers : a drug which reduces mental tension and
produces calmness without inducing sleep or depressing
mental functions (this term used to describe the effects
of reserpine/ chlorpromazine).

• Types:
– Major tranquilizers: chlorpromazine-like drugs

– Minor tranquilizers: diazepam-like drugs

 History of antipsychotic drugs
• Antipsychotic drugs have been used in Western medicine
for more than 60 years.
• Chlorpromazine (1952) and Reserpine were the first drugs
found to be useful in schizophrenia.
• Tricyclic and MOA inhibitor antidepressant in 1957-58.
• Major novel antipsychotics are selective serotonin
reuptake inhibitor and it has been introduced in 1980s.
• Little attention was paid to Cade's report in 1949 that
Lithium could be used for excitement and mania: its
effective use started in the 1960s and now it has a unique
place in psychiatry.
 Schizophrenia - symptoms
Positive Symptoms(↑↑DA) Negative Symptoms(↓↓NMDA)
Hallucinations Blunted emotions
Delusions (bizarre, persecutory) Anhedonia
Disorganized Thought Lack of feeling
Perception disturbances
Inappropriate emotions

FUNCTION
Mood Symptoms
Cognition Loss of motivation
New Learning Social withdrawal
Memory Insight
Demoralization
Suicide
–ve and +ve symptoms of schizophrenia

Back
• Positive/active symptoms include thought disturbances,
delusions, hallucinations

• Negative/passive symptoms include social withdrawal, loss of

drive, diminished affect, paucity of speech. impaired
personal hygiene
 Prognosis of Schizophrenia

• 10% continuous hospitalization

• < 30% recovery = symptom-free for 5
years
• 60% continued problems in
living/episodic periods
 Schizophrenia Pathophysiology
Schizophrenia Pharmacologic
Pathophysiology Profile of APDs
Past Excess dopaminergic Dopamine D2-receptor
activity antagonists
Present
-Renewed interest in the Combined 5-HT2/D2
role of serotonin (5-HT) antagonists
Future
-NMDA NMDA agonists
Imbalance in cortical More selective antagonists
communication and Mixed agonist/antagonists
cortical-midbrain Neuropeptide analogs
integration, involving
multiple neurotransmitters
Dopaminergic Pathways and Innervation
 Schizophrenia - Dopamine Hypothesis
 Repeated administration of stimulants like amphetamines and
cocaine, which enhance central dopaminergic
neurotransmission, can cause a psychosis that resembles the
positive symptoms of schizophrenia.

 Low doses of amphetamine can induce a psychotic reaction in

schizophrenics in remission.

 Some early studies with postmortem tissue revealed increased

numbers of DA receptors (in particular D2-like) in schizophrenic
patients
Serotonin Hypothesis of Schizophrenia

• Hallucinogens such as LSD (lysergic acid

diethylamide) and mescaline are serotonin (5-
HT) agonists
• 5-HT2A-receptor blockade is a key factor in the
mechanism of action of the main class of
atypical antipsychotic drugs such as clozapine
and quetiapine.
• 5-HT2A-receptor modulate the release of
dopamine in the cortex, limbic region, and
striatum.
 Schizophrenia - Glutamate Hypothesis
• Preclinical as well as clinical studies provide evidence of
hypofunction of NMDA receptors as a primary, or at least, a
contributory process in the pathophysiology of schizophrenia
• Several clinical trials with agents that act at the glycine
modulatory site on the NMDA receptor have revealed consistent
reductions in negative symptoms and variable effects of
cognitive and positive symptoms
• These studies also provide evidence that suggests the effects of
clozapine on negative symptoms and cognition may be through
activation of the glycine modulatory site on the NMDA
receptor.
 ANTIPSYCHOTICS
• Pre-90’s
– “Typical”, conventional, traditional neuroleptics,
major tranquilizors
– Modeled on D2 antagonism
– EPS/TD
• Post-90’s
– “Atypical”, novel, 2nd generation
– Modeled on 5-HT2/D2 antagonism
– Less EPS, prolactin effects
– Weight gain, sedation, diabetes
 Classification of antipsychotic drugs
• PHARMACOLOGICAL CLASSIFICATION
– FIRST-GENERATION ANTIPSYCHOTIC (low potency)
• Chlorpromazine
• Prochlorperazine
• Thioridazine
– FIRST-GENERATION ANTIPSYCHOTIC (high potency)
• Fluphenazine
• Haloperidol
• Pimozide
• Thiothixene
– SECOND GENERATION ANTIPSYCHOTIC
• Aripiprazole • Olanzapine
• Asenapine • Quetiapine
• Clozapine • Paliperidone
• Iloperidone • Risperidone
• Lurasidone • Ziprasidone
 Classification of antipsychotic drugs
• CHEMICAL CLASSIFICATION
– Phenothiazines
• Aliphatic side chain: Chlorpromazine, triflupromazine
• Piperidine side chain: Thioridazine
• Piperazine side chain: Trifluoperazine, fluphenazine
– Butyrophenones: Haloperidol, Trifluperidol, Penfluridol
– Thioxanthenes: Flupenthixol
– Other heterocyclics: Pimozide, Loxapine
– Atypical antipsychotics: Clozapine, risperidone, olanzapine,
quetiapine, aripiprazole, ziprasidone
 Pharmacotherapy of metal illness
• First-generation antipsychotics
• The first-generation antipsychotic drugs (also called
conventional, typical, or traditional antipsychotics) are
competitive inhibitors at a variety of receptors, but their
antipsychotic effects reflect competitive blocking of D2
dopamine receptors.
• First-generation antipsychotics are more likely to be associated
with movement disorders, particularly for drugs that bind
tightly to dopaminergic neuroreceptors, such as haloperidol.
 Pharmacotherapy of metal illness
• Second-generation antipsychotic drugs
• The second generation antipsychotic drugs (also referred to as
“atypical” antipsychotics) have fewer extrapyramidal symptoms
(EPS) than the first-generation agents, but are associated with a
higher risk of metabolic side effects, such as diabetes,
hypercholesterolemia, and weight gain.
• The second-generation drugs appear to owe their unique
activity to blockade of both serotonin and dopamine receptors.
FIRST-GENERATION ANTIPSYCHOTIC
AGENTS/ TYPICAL ANTIPSYCHOTICS
 Pharmacology of chlorpromazine (CPZ)
• Mechanism of action
– Dopamine receptor–blocking
activity in the brain: All of the first
generation and most of the second-
generation antipsychotic drugs block
dopamine receptors in the brain and
the periphery (except clozapine-like
atypical).
– The clinical efficacy of the typical
antipsychotic drugs correlates
closely with their relative ability to
block D2 receptors in the
mesolimbic system of the brain.
Mesolimbic pathway
 Pharmacology of chlorpromazine (CPZ)
• Mechanism of action
– Blockade of dopaminergic projections to the temporal and
prefrontal areas consulting the ‘limbic system’ and in
mesocortical areas is probably responsible for the
antipsychotic action.
– Blockade of dopamine over activity in basal ganglia
produces the parkinsonian adverse effects.
 Pharmacology of chlorpromazine (CPZ)
• Chlorpromazine is a prototype agent for typical
antipsychotic agent.
• CNS: Effects differ in normal and psychotic individuals
• In normal individual CPZ • In CPZ reduces irrational
indifference to surroundings, behaviour, agitation and
paucity of thought, psychomotor aggressiveness and controls
slowing, emotional quietening, psychotic symptomatology.
reduction in initiative and Disturbed thought and behaviour
tendency to go off to sleep. are gradually normalized, anxiety
Spontaneous movements are is relieved.
minimized but slurring of speech, • Hyperactivity, hallucinations and
ataxia or motor incoordination delusions are suppressed.
does not occur. • All phenothiazines, thioxanthenes
• In normal individuals CPZ and butyrophenones have the
produces neuroleptic syndrome, same antipsychotic efficacy, but
and is quite different from the potency differs in terms of
sedative action of barbiturates. equieffective doses.
 Pharmacology of chlorpromazine (CPZ)
• CNS (in psychotic individuals):
– The sedative effect is produced promptly, while
antipsychotic effect takes weeks to develop. Moreover,
tolerance develops to the sedative but not to the
antipsychotic effect.
– Extrapyramidal motor disturbances are intimately linked to
the antipsychotic effect, but are more prominent in the high
potency compounds and least in thioridazine, clozapine and
other atypical antipsychotics.
– Chlorpromazine lowers seizure threshold and can precipitate
fits in untreated epileptics.
 Pharmacology of chlorpromazine (CPZ)
• ANS:
– ANS effect of antipsychotic agents are complex and
unpredictable. Neuroleptics have varying degree of alpha
adrenergic blocking activity. Chlorpromazine, clozapine, and
thioridazine have particularly significant alpha adrenergic
antagonistic activity.
– phenothiazines have weak H1-antihistaminic and anti-5-HT
action.
• Effects on Sleep: Antipsychotic drugs have inconsistent
effects on sleep patterns but tend to normalize sleep
disturbances characteristic of many psychoses and
mania.
 Pharmacology of chlorpromazine (CPZ)
• Local anaesthetic: Chlorpromazine is as potent a local
anaesthetic as procaine. Because of its irritation action
CPZ is not used for this purposes and also its having
weaker/ no membrane stabilizing action.
• Cardiovascular System:
– Chlorpromazine has complex actions on the cardiovascular
system, directly affecting the heart and blood vessels and
indirectly acting through CNS and autonomic reflexes.
– Chlorpromazine and less potent antipsychotic agents, as well
as reserpine, risperidone, and olanzapine, can cause
orthostatic hypotension.
– Partial tolerance develops after chronic use. Reflex tachycardia
accompanies hypotension. Arrhythmia may occur in overdose
especially with thioridazine.
 Pharmacology of chlorpromazine (CPZ)
• Skeletal muscle: Neuroleptics have no effect on muscle
fibers or neuromuscular transmission. They reduce certain
types of spasticity : the site of action being in the basal
ganglia or medulla oblongata. Spinal reflex are not
affected.
• Kidney and Electrolyte Balance: Chlorpromazine may
have weak diuretic effects in animals and human beings
because of a depressant action on the secretion of
vasopressin (antidiuretic hormone), inhibition of
reabsorption of water and electrolytes by a direct action
on the renal tubule, or both.
 Pharmacology of chlorpromazine (CPZ)
• Endocrine:
– Neuroleptics consistently increase prolactin release by
blocking the inhibitory action of DA on pituitary lactotropes.
This may result in galactorrhoea and gynaecomastia. They
reduce gonadotropin secretion, but amenorrhoea and
infertility occur only occasionally.
– ACTH release in response to stress is diminished-
corticosteroid levels fail to increase under such
circumstances. Release of GH is also reduced but this is not
sufficient to cause growth retardation in children or to be
beneficial in acromegaly.
– Decreased release of ADH may result in an increase in urine
volume. A direct action on kidney tubules may add to it, but
Na+ excretion is not affected.
 Pharmacology of chlorpromazine (CPZ)
• Pharmacokinetics:
– Some antipsychotic drugs have erratic and unpredictable patterns
of absorption after oral administration.
– Parenteral (intramuscular) administration increases the
bioavailability of active drug four- to ten fold.
– Most antipsychotic drugs are highly lipophilic, highly membrane-
or protein-bound, and accumulate in the brain, lung, and other
tissues with a rich blood supply.
– They also enter the fetal circulation and breast milk. It is virtually
impossible and usually not necessary to remove these agents by
dialysis.
– Volume of distribution is large 20 L/kg and metabolized in liver by
CYP2D6; elimination t1/2 is variable (18-30 hr).
– Tolerance to the sedative and hypotensive action develops within
day or week.
Uses of chlorpromazine (CPZ)
 CLINICAL USES
• Schizophrenia
• The major use of antipsychotic drugs is in the
treatment of schizophrenia and other psychotic
disorders .
• The traditional neuroleptics are most effective in
treating positive symptoms of schizophrenia
(delusions, hallucination and thought disorders).

36
 CLINCAL USES
• Nausea and Vomiting :
• The neuroleptics (most commonly prochlor-perazine), are useful in
treatment of drug induced nausea.
• Other uses :
• Neuroleptics are used in combination with narcotic analgetics for
treatment of chronic pain with severe anxiety.
• Chlorpromazine is used to treat intractable hiccups.
• Droperidol is a component of neuroleptanesthesia.
• (a state of neuroleptanalgesia and unconsciousness, produced by the
combined administration of an opioid analgesic and a neuroleptic
(antipsychotic agent), together with the inhalation of nitrous oxide and
oxygen)
• Prometathazine is not a good antipsychotic drug, but the agent is used in
treating pruritus because of its antihistaminic properties.

37
 Adverse Effects - EPS
Details on two main extrapyramidal disturbances (EPS):
• Parkinson-like symptoms
– tremor, rigidity
– direct consequence of block of nigrostriatal DA2 R
– reversible upon cessation of antipsychotics

• Tardive dyskinesia
• involuntary movement of face and limbs
• less likely with atypical antipsychotics (AP)
• appears months or years after start of AP
• ? result of proliferation of DA R in striatum
» presynaptic?
• treatment is generally unsuccessful
Weight gain – 40% - weight gain now attributed to ratio
of binding to D2 and 5-HT2 receptors; possibly also
histamine (for newer antipsychotics anyway)
Sexual dysfunction
• result from NE and SE blockade
• erectile dysfunction in 23-54% of men
• retrograde ejaculation in
• loss of libido and anorgasmia in men and women

Seizures - <1% for generalized grand mal

Neuroleptic malignant syndrome (1-2% early in trt)
• combination of motor rigidity, hyperthermia, and
autonomic dysregulation of blood pressure and heart rate
(both go up)
• can be fatal in 5-20% of cases if untreated
• treatment – discontinue meds; give trts for fever and
cardiac problems
 Neurological Side Effects of antipsychotics
REACTION FEATURES TIME OF PROPOSED TREATMENT
MAXIMAL RISK MECHANISM

Acute dystonia Spasm of muscles of 1 to 5 days Unknown Diphenhydramine,

tongue, face, neck, promethazine
back; may mimic
seizures; not
hysteria
Akathisia Motor restlessness; 5 to 60 days Unknown Reduce dose or
not anxiety or change drug:
"agitation" antiparkinsonian
agents,
benzodiazepines or
propranololc may
help
Parkinsonism Bradykinesia, 5 to 30 days Antagonism Antiparkinsonian
rigidity, variable of dopamine agents helpful-
tremor, mask facies, trihexyphenidyl,
shuffling gait procyclidine,
benztropines
a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine
hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by
oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral
antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-
adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+
transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).
 REACTION FEATURES TIME OF PROPOSED TREATMENT
MAXIMAL RISK MECHANISM

Neuroleptic Catatonia, stupor, Weeks; can Antagonism Stop neuroleptic

malignant fever, unstable blood persist for days of dopamine immediately:
syndrome pressure, after stopping may dantrolene or
myoglobinemia; can neuroleptic contribute bromocriptine may
be fatal help:
antiparkinsonian
agents not effective

Perioral tremor Perioral tremor (may After months or Unknown Antiparkinsonian

("rabbit" be a late variant of years of agents often help
syndrome) parkinsonism) treatment

Tardive dyskinesia Oral-facial After months or Excess Stop neuroleptics,

dyskinesia; years of function of then Diazepam,
widespread treatment (worse dopamine Change to
choreoathetosis or on withdrawal) hypothesized clozapine/olanzapine
dystonia ,
Sensitivity to sun
• some phenothiazines collect in skin (chlorpromazine)
• sunlight causes pigmentation changes – grayish-purple
(look bruised)
•in eye, brown cornea, brownish cloud to vision and
possibly permanent impairment
Agranulocytosis - <1% (with clozapine)
• reduced white blood cell count
• lowered resistance to infection
• can be fatal
Jaundice – elevated bilirubin in liver - < ½%
Limitations Of Conventional Antipsychotics

 Approximately one-third of patients with

schizophrenia fail to respond

 Limited efficacy against

 Negative symptoms
 Affective symptoms
 Cognitive deficits

 High proportion of patients relapse

 Side effects and compliance issues

Antipsychotic Drugs – New Generations “atypical”

About 40-60% do not respond to phenothiazines or

cannot handle side effects
• Questions remain about the efficacy of phenothiazines
and haloperidole for negative symptoms
• Drugs needed that are low in extrapyramidal side
effects and at least equal in efficacy for positive
symptoms, perhaps better for negative
 Distinctive features of neuroleptics
Typical antipsychotic Distinctive features of neuroleptics
agent
Triflupromazine A aliphatic side phenothiazine; more potent than CPZ. Used mainly
as antiemetic
Thioridazine A low potency Phenothiazine having marked central
anticholinergic action. Risk of eye damage limits long-term use
Trifluoperazine, A high potency piperazine side chain of Phenothiazine. They have
fluphenazine minimum autonomic actions and cause jaundice (ADR).
Haloperidol It is a potent antipsychotic with pharmacological profile
resembling that of piperazine substituted phenothiazines.
Trifluperidol It is similar to but slightly more potent than haloperidol.
Penfluridol exceptionally long acting neuroleptic, recommended for chronic
schizophrenia
Flupenthixol Infrequently used now.
Pimozide It is a specific DA antagonist with little alpha adrenergic or
cholinergic blocking activity. It has been particularly used in Gilles
de la Tourette's syndrome and ticks.
Loxapine A dibenzoxazepine having CPZ like DA blocking and antipsychotic
activity
 Haloperidol
• It is typical antipsychotic agent.
• Used for the treatment of
– nonstop talking and apparent loss of contact with reality.
– Tourette syndrome
– hallucinations in alcohol withdrawal
SECOND -GENERATION ANTIPSYCHOTIC
AGENTS

or

ATYPICAL ANTIPSYCHOTICS
 second -generation antipsychotic agents

• Second generation antipsychotics have weak D2 blocking but

potent 5-HT2 antagonistic activity. Extrapyramidal side effects
are minimal, and they may improve the impaired cognitive
function in psychotics.
 Clozapine
• First atypical antipsychotic agent; Week D2 blocking action; few/no
extrapyramidal effects
• Both –ve and +ve symptoms of schizophrenia are improved; used as
a reserve drug in resistant schizophrenia.
• The differing pharmacological profile may be due to its relative
selectivity for D4 receptors (which are sparse in basal ganglia) and
additional 5-HT2 as well as a blockade.
• Clozapine is metabolized primarily by CYP3A4 with an average t1/2 of
12 hours. Its major limitation is higher incidence of agranulocytosis
(0.8%) and other blood dyscrasias; weekly monitoring of leucocyte
count is required. High dose can induce seizures even in
nonepileptics. Other side effects are sedation, unstable BP,
tachycardia, urinary incontinence, weight gain and precipitation of
diabetes.
Agranulocytosis is a rare condition that occurs when the bone marrow does not make enough
neutrophils
 Risperidone
• Combination of D2 + 5-HT2 receptor blockade.
• In addition it has high affinity for α1, α2 and H1 receptors; blockade
of these may contribute to efficacy as well as side effects like
postural hypotension.
• Risperidone is more potent D2 blocker than clozapine;
extrapyramidal side effects are less only at low doses ( <6 mg/
day). Prolactin levels rise during risperidone therapy, but it is
less epileptogenic than clozapine.
• Caution: increased risk of stroke in the elderly.
 Olanzapine
(broader spectrum of efficacy covering schizo-affective disorders)

• Resembles clozapine in blocking multiple monoaminergic (D2,

5-HT2, α1, α2) as well as muscarinic and H1 receptors. Both
positive and negative symptoms of schizophrenia appear to be
benefited.
• A broader spectrum of efficacy covering schizo-affective
disorders, and it is approved for use in mania. Monotherapy
with olanzapine may be as effective as a combination of
lithium/valproate + benzodiazepines.
• Weaker D2 blockade results in few extrapyramidal side effects
and little rise in prolactin levels.
• Incidence of stroke may be increased in the elderly.
• Agranulocytosis has not been reported with olanzapine.
• Olanzapine is metabolized by CYP1A2 and glucuronyl
transferase. The t1/2 is 24-30 hours.
 Quetiapine
• This new short-acting (t1/2 is 6 hours) atypical antipsychotic
requires twice daily dosing.
• It blocks 5-HT1A, 5-HT2, D2, α1, α2 and H1 receptors in the
brain, but D2 blocking activity is low: extrapyramidal and
hyperprolactinaemic side effects are minimal.
• ADR:
– quite sedating, postural hypotension, urinary retention
– Weight gain and rise in blood sugar are infrequent
• Use: benefit negative symptoms of schizophrenia, but can be
used in mania /bipolar disorder.
• It is metabolized mainly by CYP3A4; can interact with
macrolides, antifungals, anticonvulsants, etc.
 Atypical Distinctive features
antipsychotic agent
Aripiprazole • partial agonist at D2 and 5-HT1A receptor
• It is minimally sedating, may even cause insomnia
• Metabolized by CYP2D6 and CYP3A4.
• ADR: nausea, dyspepsia, constipation and light-headedness.
hyperprolactinaemia, hypotension and Q-T prolongation are
not frequent.
Ziprasidone • D2 + 5-HT2A/2C + H1 + α1 receptor blocking activity.
• Efficacy in schizophrenia has been related equivalent to
haloperidol
Amisulpiride • Congener of sulpiride (typical antipsychotic)
• High affinity to D2 (and D3) receptor and has low affinity for 5-
HT2 receptor.
• Not sedative.
Zotepine • D1+D2 and 5-HT2, α1 receptor blocking activity.
• It also inhibits NA reuptake.
• Both positive and negative symptoms of schizophrenia appear
to be benefited.
• It has lower seizure threshold.
• ADR: Weight gain, hyperglycemia.
Adverse events
 Adverse events
• CNS: Drowsiness, lethargy, mental confusion, weight gain (not
with haloperidol), aggravation of seizures in epileptics.
• CVS: Postural hypotension, palpitation, inhibition of ejaculation
(especially with thioridazine) are due to a adrenergic blockade; Q-
T prolongation and cardiac arrhythmias are risk of overdose with
thioridazine, pimozide and ziprasidone.
• Anticholinergic Dry mouth, blurring of vision, constipation, urinary
hesitancy in elderly males.
• Endocrine Hyperprolactinemia (due to D2 blockade) is common
with typical neuroleptics and risperidone. This can lower GH
levels, but amenorrhoea, infertility, galactorrhoea and
gynaecomastia occur infrequently after prolonged treatment.
• Metabolic effect: Elevation of blood sugar and triglyceride.
 Adverse events
• Extrapyramidal disturbances: Dose-limiting side effects.
– The inhibitory effects of dopaminergic neurons are normally balanced by
the excitatory actions of cholinergic neurons in the striatum. Blocking
dopamine receptors alters this balance, causing a relative excess of
cholinergic influence, which results in extrapyramidal motor effects.
– Parkinson-like symptoms of bradykinesia, rigidity, and tremor usually
occur within weeks to months of initiating treatment. Tardive dyskinesia,
which can be irreversible, may occur after months or years of treatment.
• Hypersensitivity reaction: Chlestatic jaundice, myocarditis,
agranulocytosis.
• Miscellaneous: Weight gain often occurs with long term
antipsychotic therapy; blood sugar and lipids may tend to rise. Risk
of worsening of diabetes and blue pigmentation of exposed skin,
and retinal degeneration.
Tardive dyskinesia is a disorder that involves involuntary movements, especially of the lower
face (tongue, lips, face, trunk, and extremities).
 UNWANTED EFFECTS
1.”Extrapyramidal” reactions
include
a) Parkinsonism : usually
of mild degree responds
to anticholinergic drugs or
amantadine.
b) Akathisia : is a subjective
sense of restlessness
usually (inability to sit)
accompanied by mild to
moderate motor
hyperactivity, usually
responds to α-adrenergic
receptor antagonists,
anticholinergics,
antihistamines or
amantadine.

29
 UNWANTED EFFECTS
Acute dystonia :
• Due to the blocked of DA-
nergic nigrostriatal
pathway.
• Reactions are involuntary
movements
(restlessness,muscle
spasms, protruding tongue,
fixed upward gaze,
torticollis, etc.)
• Occur commonly in the first
few weeks, often declining
with time, and are
reversible on stopping
treatment.

30
 UNWANTED EFFECTS
• Tardive dyskinesia :
• develops after months or years in
20-40% of patients treated with
typical antipsychotic drugs
• Irreversible and highly disabling.
• Involuntary and excessive oral-
facial movements but also of
trunk n limbs.
• it is associated with a gradual
increase in the number of D2
receptor in striatum (up-
regulation), which is less marked
with the atypical antipsychotic
drugs.

31
 UNWANTED EFFECTS
2.Endocrine effects
• DA released by neurons of the tuberoinfundibular pathway acts via D2
receptors as an inhibitor of prolactin.Thus blocking D2 receptors
therefore increases the plasma prolactin concentration, resulting
breast swelling, pain and lactation, which can occur in men as well as
women.
3. Neuroleptic malignant syndrom :
• Rare but serious complication.
• It occurs in 1% to 2% of patients and is fatal in almost 10% of those
affected.
• This is observed early in treatment and is characterized by a near
complete collapse of the autonomic nervous system, causing, for
example, fever, muscle rigidity, diaphoresis, mental confusion and
cardiovascular instability.
• Immediate medical intervention with bromcriptine (DA agonist) and

32
dantrolene is nessesary.
 UNWANTED EFFECTS
4. Sedation:
• Tends to decrease with continued use. Antihistaminic (H1) property of
phenothiazines contributes to their sedative and antiemetic properties.
5.Peripheral effects.
• Blocking muscarinic receptors : produce blurring of vision and
increased intraocular pressure, dry mouth and eyes, constipation and
urinary retention.
• Blocking α-adrenoreceptors : orthostatic hypotension.
• Weight gain is a common and troublesome side-effect, probably
related to 5-HT antagonism.

33
 UNWANTED EFFECTS
6.Idiosyncratic and hypersensitivity Reactions :
• Jaundice:
• with older phenothizines, such as chlorpromazine.
• usually mild,obstructive and reversible
• Leukopenia and agranulocytosis :
• rare, but potentially fatal, and occur in the first few weeks.
• The incidence of leukopenia (usually reversible) is higher (1-2%) with
clozapine,provided the drug is stopped at the first sign of leukopenia or
anemia, the effect is reversible.
• Olanzapine appears to be free of this disadvantage.
• Urticarial skin reactions are common but usually mild. Excessive
sensitivity to ultraviolet light may also occur.

34
Thank you